Diagnostic dilemmas in hepatoid adenocarcinoma of the stomach: Navigating clinical and pathological loopholes

Table 1 Diagnostic challenges and key features in hepatoid adenocarcinoma of the stomach

Domain	Challenges/features	Clinical implications
Clinical presentation	Nonspecific symptoms: Epigastric discomfort, weight loss, GI bleeding. Mimics benign conditions and conventional gastric cancer	Delayed diagnosis and referral; missed opportunity for early intervention
Imaging	CT/MRI may resemble HCC due to arterial phase hyperenhancement; PET-CT has low sensitivity in well-differentiated tumors	High risk of misdiagnosing metastatic liver lesions as primary HCC
Serum AFP	Elevated in 70%-80% of HAS but also seen in HCC, yolk sac tumors, and benign liver conditions; some HAS cases are AFP-negative	AFP is supportive but unreliable alone; can lead to diagnostic misdirection
Histopathology	Mixed histological features; hepatoid areas may be focal and missed in small biopsies; overlaps with other poorly differentiated tumors	Requires experienced pathological evaluation and possibly repeated/deep biopsies
IHC	Variable expression of markers (AFP, HepPar-1, Glypican-3, SALL4); SALL4 is more reliable but not entirely specific	IHC is essential but must use a panel approach; no single definitive marker
Biopsy limitations	Superficial biopsies often miss deeper hepatoid components; tumor heterogeneity adds complexity	Multiple and deeper biopsies (e.g., EUS-guided) recommended for accurate sampling
Differential diagnosis	Overlaps with metastatic HCC, yolk sac tumors, and poorly differentiated gastric adenocarcinomas	Multidisciplinary approach is crucial to avoid misclassification and mistreatment
Lack of standardized criteria	No universally accepted diagnostic benchmarks (e.g., reliance on morphology vs AFP vs IHC); variable institutional practices	Inconsistent diagnosis, hindered research comparisons, and variable treatment strategies
Misdiagnosis consequences	Incorrect treatment strategy (e.g., targeting liver primary), delayed curative options, clinical trial exclusion	Worsened prognosis and lost therapeutic opportunities
Recommendations	Use structured workflow: Clinical suspicion; imaging + deep biopsy; full IHC panel (SALL4, AFP, HepPar-1, Glypican-3); and multidisciplinary review; explore molecular diagnostics	Improves early detection, diagnostic accuracy, and patient outcomes

IHC: Immunohistochemistry; MRI: Magnetic resonance imaging; HCC: Hepatoid adenocarcinoma; PET: Positron emission tomography; EUS: Endoscopic ultrasound; AFP: Alpha-fetoprotein; GI: Gastrointestinal; HAS: Hepatoid adenocarcinoma of the stomach.